1. Field of the Invention
The invention relates to a medicine, and in particular to a huperzine A compound used in the treatment of Alzheimer's disease.
2. Description of the Related Art
Alzheimer's disease (AD) accounts for about 75% of aged dementia. This central nervous system disorder is marked by a variety of symptoms such as degeneration of neurons, development of amyloid plaque, neurofibrillary tangle, and declination of acetylcholine and atrophy of cerebral cortex. Patients with AD initially suffer from short-term memory loss, followed by a drop in cognitive function and finally, lose the ability to care for themselves.
AD affects about 10% of the population beyond age 65. It attacks 19% of individuals 75 to 85 years old, and 45% over age 85. AD is the fourth leading cause of death in adults, behind heart disease, cancer, and stroke. The cost of caring for patients, including diagnosis, nursing, at-home care, and lost wages combined, is estimated to be 40 to 90 billion US dollars per year.
Although there has been great progress in understanding the pathophysiologic mechanisms of the disease, the causes of AD are still poorly understood. Possible causes include genetic predisposition, neurotransmitter defects, inflammation, metabolic decline, oxidative stress, and excitatory amino acid toxicity; none of these causes however, is alone conclusive.
Several compounds are currently used in clinical practice for the treatment of AD according to the current understanding of its pathogenesis. Among these drugs, notable are acetylcholine esterase (AchE) inhibitors. AchE inhibitors, such as donepezil, rivastigmine, tacrine, galantamine and huperzine A (huperzine A) all have received regulatory approval for AD treatment in a variety of countries.
Huperzine A is an alkaloid isolated from Lycopodium serratum, a Chinese traditional medicinal herb. Huperzine A appears to be more specific and potent in inhibiting AchE compared to tacrine and donepezil as demonstrated in both in vitro and in animal models. The three-dimensional crystal structure of the AchE/huperzine A complex shows a strong hydrophobic interaction between huperzine A and the active-site pocket of AchE. Further studies have revealed that huperzine A is capable of penetrating the blood-brain barrier to produce a dose-dependent increase of Ach, norepinephrine, and dopamine in rat cortex by systemic or local administration of huperzine A. It also appears that huperzine A demonstrates promising effects in protecting neurons from neurotoxins. Evidence obtained from studies employing rat embryo hippocampus and cerebellum cultured cells have revealed that huperzine A decreases the death of neuronal cell caused by toxic levels of glutamate. The pharmacokinetic evaluation of a single oral dose of huperzine A to volunteers showed that huperzine A was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate. In a small double blind clinical study conducted in China, huperzine A administered orally at 0.2 mg twice a day for 8 weeks had demonstrated significant improvement in memory, cognition and behavior in 58% patients without causing any severe side effects to the volunteers.
Because huperzine A is rapidly eliminated from the kidneys, its half-life in plasma is only 4 to 5 hours. Thus, the clinical oral dosage of huperzine A for treatment of Alzheimer's disease varies from 5 to 20 mg with a dose frequency of 2-4 times per day. One important concern in the administration of drugs for AD is convenience of self-medication for patients as well as caregivers, particularly elderly patients suffering from dementia or memory disorders. Repeated administration of drugs may be troublesome with these patients as they tend to forget to take the medication at the scheduled time or otherwise may require a caregiver to ensure the medication schedule is maintained. Thus, means for achievements of conveniently administration of drug and keeping medication at the scheduled time, administration of huperzine A to AD patients once-daily is highly desirable.
Another important factor in determining whether AD patients maintain medication schedules is drug adverse reactions. Available data indicate that the adverse effects of huperzine A at therapeutic dosages are primarily cholinergic and include nausea, vomiting, diarrhea, hyperactivity, dizziness, and anorexia. Clinically important bradycardia was also noted in one clinical study and may form a problem for patients with existing cardiac disease. The causes of these adverse effects may be due to the excellent absorption and wide distribution of huperzine A as well as rapid penetration into the brain to produce a rapid increased acetylcholine level. Thus, a means for controlled exposure of huperzine A to AD patients capable of reducing adverse effects is highly desirable.
Several conventional huperzine A compounds, their structures and applications thereof have been disclosed, for example, by U.S. Pat. No. 4,929,731, U.S. Pat. No. 5,104,880, U.S. Pat. No. 5,106,979, U.S. Pat. No. 5,177,082, U.S. Pat. No. 5,547,960, U.S. Pat. No. 5,663,344, U.S. Pat. No. 5,869,672, U.S. Pat. No. 5,929,084, U.S. Pat. No. RE38460, WO 99/11625 and WO 2007/014498.